Purinyl or pyrimidinyl substituted hydroxycyclopentane compounds useful as antivirals

ABSTRACT

Novel 4-substituted-5-hydroxymethyl-1,2-cyclopentanediols or 1-cyclopentanol substituted at the 3-position by various heterocyclic groups are useful as antiviral agents.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to4-substituted-5-(hydroxymethyl)-1,2-cyclopentanediols and1-cyclopentanols substituted at the 3-position by various heterocyclicgroups and the pharmaceutically acceptable acid addition salts thereofwhich are useful as antiviral agents. The invention also relates topharmaceutically acceptable composition containing an effective amountof at least one of the compounds. The invention also relates to aprocess for making the compounds of the invention.

2. Related Disclosure

Aristeromycin and certain aristeromycin derivatives are known. See, forexample, Japanese Pat. No. 7023596, Japanese Patent Application No.57094288, U.S. Pat. No. 4,177,348, U.S. Pat. No. 4,138,562, U.S. Pat.No. 4,232,154, U.S. Pat. No. 4,396,623 and European Pat. No. 104,066. Anovel class of 5-hydroxymethyl-1,2-cyclopentanediols and1-cyclopentanols wherein the 4-position of the cyclopentane ring issubstituted has now been prepared.

SUMMARY OF THE INVENTION

The first aspect of the invention is the group of compounds representedby the formula: ##STR1## wherein A is hydroxy; and

C is hydrogen or hydroxy;

B is a heterocyclic ring selected from the group consisting of2-amino-6-hydroxypurin-9-yl, 6-aminopurin-9-yl, 2,4-dioxopyrimidin-1-yloptionally substituted at the 5-position by fluoro, methyl, iodo,trifluoromethyl, 2-bromovinyl. 2-chlorovinyl or 2-iodovinyl, and4-amino-2-oxopyrimidin-1-yl optionally substituted at position-5 by iodoor trifluoromethyl;

Z is hydrogen and Z' is hydroxy or fluoro; or

Z and Z' are both fluoro; or

Z together with Z' is oxo; and

the wavy line indicates that the group may be above or below the planeof the ring; and

the pharmaceutically acceptable acid addition salts thereof.

The second aspect of the invention is a composition useful for treatingRNA and DNA viral infections which composition comprises an effectiveamount of at least one compound of formula (I) or compound of formula(XIII) or a pharmaceutically acceptable acid addition salt thereof and apharmaceutically acceptable excipient.

Another aspect of the invention is a method for treating warm-bloodedand cold-blooded animals for RNA and DNA viral infections which compriseadministering an effective amount of at least one compound of formula(I) or compound of formula (XIII).

Another aspect of the invention is a process for preparing the compoundsof the formula: ##STR2## wherein A is hydroxy; and

C is hydrogen or hydroxy;

B is a heterocyclic ring selected from the group consisting of2-amino-6-hydroxypurin-9-yl, 6-aminopurin-9-yl, 2,4-dioxopyrimidin-1-yloptionally substituted at the 5-position by fluoro, methyl, iodo,trifluoromethyl, 2-bromovinyl. 2-chlorovinyl or 2-iodovinyl, and4-amino-2-oxopyrimidin-1-yl optionally substituted at position-5 by iodoor trifluoromethyl;

Z and Z' are independently hydrogen, fluoro, hydroxy or Z together withZ' is oxo;

the wavy line indicates that the group may be above or below the planeof the ring; and

the pharmaceutically acceptable acid addition salts thereof.

Another aspect of the invention is the compound of the formula ##STR3##wherein X is oxygen or NH, Y is hydrogen, iodo, fluoro, methyl ortrifluoromethyl;

Z is hydrogen or fluoro and Z' is fluoro;

and the wavy line indicates that the group may be above or below theplane of the ring;

and the pharmaceutically acceptable acid addition salts thereof.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENT

The broadest aspect of the present invention is the group of compoundsrepresented by the formula: ##STR4## wherein A is hydroxy; and

C is hydrogen or hydroxy;

B is a heterocyclic ring selected from the group consisting of2-amino-6-hydroxypurin-9-yl, 6-aminopurin-9-yl, 2,4-dioxopyrimidin-1-yloptionally substituted at the 5-position by fluoro, methyl, iodo,trifluoromethyl, 2-bromovinyl, 2-chlorovinyl or 2-iodovinyl, and4-amino-2-oxopyrimidin-1-yl optionally substituted at position-5 by iodoor trifluoromethyl;

Z and Z' are independently hydrogen, fluoro, hydroxy or Z together withZ' is oxo;

the wavy line indicates that the group may be above or below the planeof the ring; and

the pharmaceutically acceptable acid addition salts thereof.

Another aspect of the present invention are the compounds of the formula##STR5## wherein X is oxygen or NH, Y is hydrogen, iodo, fluoro, methylor trifluoromethyl;

Z is hydrogen or fluoro and Z' is fluoro;

and the wavy line indicates that the group may be above or below theplane of the ring;

and the pharmaceutically acceptable acid addition salts thereof.

A preferred group of compounds of formula (I) is that wherein B is2,4-dioxo-5-fluoropyrimidinyl or 2,4-dioxopyrimidinyl and A and C areboth hydroxy. Within this group it is preferred that at least one Z orZ' is fluoro.

Another preferred group of compounds of formula (I) is that wherein A ishydroxy and C is hydrogen and B is 2,4-dioxoprymidinyl substituted inthe 5-position by iodo, fluoro, trifluoromethyl, 2-bromovinyl or2-iodovinyl.

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated."Heterocyclic ring precursor" is a group which can be cyclized to thegroup "B" of the instant compounds. "Alkoxy" refers to the group R'O-wherein R' is an alkyl group of one to four carbon atoms.

In naming the compounds of the instant invention the following numberingsystems for the rings will be used: ##STR6## It is understood that agroup above the plane of the ring is signified by "β" and the groupbelow the plane of the ring is signified by "α".

It is further understood that the definition of X as hydroxy or amino onthe pyrimidine ring also encompasses the tautomeric oxo form or iminoform.

Compounds of formula (I) may exist as stereoisomers.

Certain compounds of the present invention possess asymmetric carbonsand may be prepared in either optically active form, or as a racemicmixture. Unless otherwise specified, such compounds described herein areall in the racemic form. However, the scope of the subject inventionherein is not to be considered limited to the racemic form but toencompass the individual optical isomers of the subject compounds.

If desired, racemic products prepared herein may be resolved into theiroptical antipodes by conventional resolution means known per se, forexample, by the separation (e.g., fractional crystallization) of thediastereomeric esters formed by reaction of, e.g. racemic compounds offormula (I) with an optically active acid or acid chloride. Exemplary ofsuch optically active acids and acid chlorides are the optically activeforms of camphor-10-sulfonic acid, α-bromocamphor-π-sulfonic acid,camphoric acid, menthoxyacetic acid, tartaric acid, malic acid,diacetyltartaric acid, 6-methyoxynaphth-2-yl-2-propanoyl chloride,pyrrolidone-5-carboxylic acid, dibenzoyltartaric acid, and the like. Theseparated pure diastereomeric esters may then be cleaved by standardmeans to afford the respective optical isomers of the compounds offormula (I).

Another method of preparing the optical isomers of compounds of formula(I) is by separating the racemic intermediate of formula (VIII) into theindividual isomers by the methods described above and then proceedingwith the individual isomers to prepare the optically active compounds offormula (I)

UTILITY AND ADMINISTRATION

The subject compounds of formula (I) and formula (XIII) exhibit potentantiviral activity against both RNA and DNA viruses when administered towarm blooded and cold blooded animals, particularly mammals, birds, andfish, but most particularly humans. For example, the compounds of thepresent invention exhibit excellent activity against Herpes Simplexvirus I and II and related viruses such as cytomegalovirus, Epstein-Barrvirus and varicella Zoster virus as well as viral hepatitis such ashepatitis B.

The compounds of the instant invention are also active againstinfluenza, parainfluenza, rhino and respiratory syncytial viruses.

Pharmaceutical compositions, both veterinary and human, containing thesubject compound appropriate for antiviral use are prepared by methodsand contain excipients which are well known in the art. A generallyrecognized compendium of such methods and ingredients is Remington'sPharmaceutical Sciences by E. W. Martin, (Mark Publ. Co., 15th Ed.,1975). Liposomes may also be employed as pharmaceutical compositions forthe compounds of formula (I), using methods known to those in the art[for example, as described in Szoka, F. Jr. et al,Ann.Rev.Biophys.Bioeng. 9:467-508 (1980), Schullery, S. E. et al,Biochemistry 19: 3919-3923 (1980) and Gregoriadis, G. et al, "Liposomesin Biological Systems," John Wiley and Sons (1980)].

The compounds of the invention may be administered parenterally (forexample, by intravenous, subcutaneous, intraperitoneal or intramuscularinjection), orally, topically, intranasally or rectally.

The compositions are administered orally or parenterally at dose levelsof about 0.1 to 300 mg/kg of compound of formula (I) or compound offormula (XIII), preferably 1.0 to 30 mg/kg of mammal body weight, andare used in man in a unit dosage form, administered one to five timesdaily in the amount of 10 to 500 mg per unit dose. For oraladministration, fine powders or granules may contain diluting,dispersing and/or surface active agents, and may be presented in adraught, in water or in a syrup; in capsules or sachets in the dry stateor in a non-aqueous solution or suspension, wherein suspending agentsmay be included; in tablets, wherein binders and lubricants may beincluded; or in a suspension in water or a syrup. Where desirable ornecessary, flavoring, preserving, suspending, thickening or emulsifyingagents may be included. Tablets and granules are preferred, and thesemay be coated. The amount of compound of formula (I) or compound offormula (XIII) in the formulation may vary from 0.1 percent weight (%w)to 99%w or more of the compound based on the total formulation and about1%w to 99.9%w excipient. Preferably the compound is present at a levelof 10%-95%w.

For parenteral administration or for administration as drops, as for eyeinfections, the compounds may be presented in aqueous solution in aconcentration of from about 0.1 to 10%, more preferably about 0.1 to 7%.The solution may contain antioxidants, buffers, and other suitableadditives.

Alternatively for infections of the eye, or other external tissues, e.g.mouth and skin, the compositions are preferably applied to the infectedpart of the body of the patient topically as an ointment, cream, aerosolor powder, preferably an an ointment or cream. The compounds may bepresented in an ointment, for instance with a water soluble ointmentbase, or in a cream, for instance with an oil in water cream base, in aconcentration of from about 0.01 to 10%; preferably 0.1 to 7%, mostpreferably about 4.0% w/v. Additionally, viral infections may be treatedby use of a sustained release drug delivery system as is described inU.S. Pat. No. 4,217,898.

For aerosol administration, the active ingredient is preferably suppliedin finely divided form along with a surfactant and a propellant. Typicalpercentages of active ingredients are 0.01 to 50% by weight, preferably0.04 to 10.0%.

Surfactants must, of course, be non-toxic, and preferably soluble in thepropellant. Representative of such agents are the esters or partialesters of fatty acids containing from 6 to 22 carbon atoms, such ascaproic, octanoic, lauric, plamitic, stearic, linoleic, linolenic,olestearic and oleic acids with an aliphatic polyhydric alcohol or itscyclic anhydride such as, for example, ethylene glycol, glycerol,erythritol, arabitol, mannitol, sorbitol, the hexitol anhydrides derivedfrom sorbitol (the sorbitan esters sold under the trademark "Spans") andthe polyoxyethylene and polyoxypropylene derivatives of these esters.Mixed esters, such as mixed or natural glycerides may be employed. Thepreferred surface-active agents are the oleates or sorbitan, e.g., thosesold under the trademarks "Arlacel C" (Sorbitan sesquioleate), "Span 80"(sorbitan monooleate) and "Span 85" (sorbitan trioleate). The surfactantmay constitute 0.1-20% by weight of the composition, preferably 0.25-5%.

The balance of the composition is ordinarily propellant. Liquefiedpropellants are typically gases at ambient conditions, and are condensedunder pressure. Among suitable liquefied propellants are the loweralkanes containing up to five carbons, such as butane and propane; andpreferably fluorinated or fluorochlorinated alkanes, such as are soldunder the trademark "Freon." Mixtures of the above may also be employed.

In producing the aerosol, a container equipped with a suitable valve isfilled with the appropriate propellant, containing the finely dividedactive ingredient and surfactant. The ingredients are thus maintained atan elevated pressure until released by action of the valve.

The compounds of the present invention or compositions containing sameare also useful in treating non-human mammals, birds, e.g., chickens andturkeys, and cold-blooded animals, e.g., fish. For example, thecompounds of the present invention and compositions containing sameexhibit antiviral activity against the following non-human viruses:

Sciruid herpes virus 1

Cavlid herpes virus 1

Lagomorph herpes virus 1

Phasianid herpes virus 1

Phasianid herpes virus 2 (Marek's disease)

Turkey herpes virus 1

Anatid herpes virus 1

Catfish herpes virus 1

Equid herpes virus 3

Bovid herpes virus 1

Bovid herpes virus 2

Bovid herpes virus 3

Bovid herpes virus 4

Pig herpes virus 1

Pig herpes virus 2

Murid herpes virus 1

Cebid herpes virus 1

Cebid herpes virus 2

Tupaiid herpes virus 1

Canine herpes virus 1

Feline herpes virus 1

Equid herpes virus 1

Equid herpes virus 2

Avian viral diseases such as Marek's disease and the like are preventedand/or treated by compounds of the present invention by methodswell-known in the veterinary art such as by injecting the birds with thecomposition containing the compound, or by adding the compound of theinstant invention to feed or drinking water.

Fish which are in a confined area such as a pool, aquarium or holdingtank may also be treated for viral infections such as herpes-likeviruses, e.g., channel catfish virus (CCV), herpes-virus salomones,Nerka virus and the like by adding the compound directly to the water ofthe pool, aquarium or holding tank or by incorporating the compoundsinto the feed.

The compounds of the present invention are also useful for treatingmammals suffering from upper and lower respiratory tract infections suchas human and bovine RSC.

The exact regimen for administration of the compounds and compositionsdisclosed herein will necessarily be dependent upon the needs of theindividual subject being treated, the type of treatment and, of course,the judgment of the attending practitioner.

PREPARATION

The novel process for preparing compounds of formula (I') whichencompasses the compounds for formula (I) is shown below. Compounds offormula (XIII) may be prepared from compounds of formula (I). ##STR7##wherein Bn is benzyl, M is a metal, A, B, C, Z and Z' are as definedabove and R is a heterocyclic ring precursor.

Compound of formula (II), available from Alpha Chemical Co., is reactedwith benzyl chloromethyl ether to form a compound of formula (III). Thechloromethyl ether is added dropwise to a metal derivative ofcyclopentadiene, e.g., sodium, potassium or thallium, preferablythallium cyclopentadiene of formula (II) over 15 to 60 minutes,preferably over 15 to 45 minutes suspended in a solvent such as diethylether. The suspension is stirred at -25° to 0° C. for 10 to 24 hours,preferably at -25° to -15° C. for 12 to 20 hours. The suspension isfiltered and compound of formula (III) is recovered by evaporation ofthe filtrate. Without purification compound of formula (III) isdissolved in a solvent such as methanol cooled to -20° C. and oxidizedto the novel compound of formula (IV) which is reduced to compound offormula (V) in situ by adding compound of formula (III) in methanol to asolution of thiourea dissolved in a solvent such as methanol which issaturated with oxygen containing an oxygen sensitizer such as RoseBengal. The solution is held at -5° C. while it is irradiated for 5 to12 hours, preferably for 7 to 10 hours with a mercury immersion lamp.Oxygen is continuously added throughout the irradiation. Compound offormula (V) is recovered by evaporation of the solvent and purified by,e.g., chromatography.

Compounds of formula (III) may also be oxidized to compound of formula(IV) with a peroxy compound such as hydrogen peroxide and sodiumhypochlorite mixture.

Compound of formula (V) is converted to compound of formula (VI) bydissolving compound (V) in a solvent such as dichloromethane andtreating compound (V) with an oxidizing agent such as a carboxylicperoxy acid such as perbenzoic acid, m-chloroperbenzoic acid, peraceticacid, and the like. The epoxide of formula (VI) is recovered by e.g.chromatography or solvent extraction.

Compound of formula (VII) is prepared by dissolving compound of formula(VI) in a solvent such as dimethylformamide, N-methyl-2-pyrrolidone andthe like, adding an alkali metal azide, e.g., sodium azide and heatingto 50° to 150° C., preferably 80° to 120° C. for 6 to 24 hours,preferably for 8 to 16 hours. Compound of formula (VII) is recovered asan oil which is purified by e.g. chromatography.

The azide of formula (VII) is reacted with 2,2-dimethoxypropane in asolvent such as acetone and the like in the presence of a strong acidsuch as perchloric acid, hydrochloric acid and the like. The solution isstirred at room temperature to 50° C., preferably at room temperaturefor 15 minutes to 3 hours, preferably for 1/2 to 1 hour. Afterneutralizing with a base such as sodium hydroxide or ammonium hydroxide,the resulting oil is purified by, e.g., chromatography.

The azide of formula (VIII) is converted to the amine of formula (IX) bycatalytic hydrogenation.

A suspension of compound of formula (VIII) in an alcohol such asmethanol, ethanol, isopropanol and the like in the presence of thecatalyst such as palladium on calcium carbonate is maintained under apositive hydrogen pressure for 6 to 24 hours, preferably for 8 to 16hours. After removal of the catalyst compound of formula (IV) wherein Zis OH and Z' is hydrogen is recovered by, e.g., chromatography. Compoundof formula (IX) wherein Z is fluoro and Z' is hydrogen is prepared byreacting the hydroxy group at position-4 with a sulfonic acid anhydrideor sulfonic acid chloride such as trifluoromethanesulfonic anhydride,methanesulfonic anhydride, toluenesulfonic chloride and the likefollowed by reaction with a fluorinating agent such astris(dimethylamino)sulfonium difluorotrimethylsilicate. Compound offormula (VIII) in a solvent such as dichloromethane and a sulfonicanhydride or chloride is stirred at room temperature for 15 minutes to 2hours, preferably for 30 minutes to 11/2 hours. The solvent is removedand the sulfonate of compound of formula (VIII) is recovered.

The sulfonate in a solvent such as tetrahydrofuran and the like isfluorinated with, e.g., tri(dimethylamino)sulfoniumdifluorotrimethylsilicate available, i.a., from Aldrich Chemical Co. Thesolution is heated under reflux for 6 to 24 hours, preferably for 8 to16 hours. The azide group is reduced to the amino group by the methoddescribed above. Compound of formula (IX) wherein Z is fluoro and Z' ishydrogen is recovered and purified by, e.g., chromatography. Where Ztogether with Z' is oxo compound of formula (IX) is prepared byoxidizing compound of formula (VIII) with, e.g., pyridinium chlorochromate. Where Z and Z' are both fluoro compound of formula (IX) isprepared by the method described in J. Org. Chem., 40(5):574 (1975).

When both Z and Z' are hydrogen, compound of formula (IX) is prepared byfirst converting the 4-hydroxy group to a sulfonate group by the methoddescribed above. This compound is reacted with lithium iodide in asolvent such as dimethylformamide and the like at room temperature for1/2 to 3 hours, preferably for 1/2 to 2 hours. The iodide compound ispurified by, e.g., chromatography and the iodide group is removed bycatalytic hydrogenation. The iodide compound in a solvent such asmethanol is shaken in a Parr bomb in the presence of, e.g., palladium oncarbon and hydrogen at room temperature for 2 to 12 hours, preferablyfor 3 to 8 hours. The azide group is also reduced to the amino group.

Compound of formula (IX) is reacted with a reagent which yields a group,R, to form compound of formula (X). Compound of formula (X) is cyclizedto compound of formula (XI).

When the desired B is an optionally substituted purine ring, compound offormula (IX) is reacted with 5-amino-4,6-dichloropyrimidine to formcompound of formula (X) wherein R is 5-amino-6-chloropyrimidin-4-yl.Compound of formula (IX) in a solvent such as N-methylpyrrolidone andthe like in the presence of a base such as pyridine, triethylamine andthe like are reacted with 5-amino-4,6-dichloropyrimidine at 100° to 220°C., preferably at 150° to 200° C. for 6 to 24 hours, preferably for 8 to16 hours. Compound of formula (X) is recovered by extraction andchromatography.

Another method for preparing compounds of formula (XI) wherein Z and Z'are both hydrogen is by reacting compound of formula (XI) wherein Z ishydroxy and Z' is hyrogen with 1,1-diimidazolylthiocarbonyl to form theintermediate of formula (XI) wherein the 4-position is substituted by1-imidazolylthiocarbonyloxy group. The 1-imidazolylthiocarbonyloxy groupis removed by reduction with tributyl tin hydride.

Compound of formula (XI) wherein B is an optionally substituted purineis prepared from compound of formula (X) wherein R is5-amino-6-chloropyrimidin-4-yl by reacting with diethoxymethylacetate ortrialkyl orthoformate, preferably trimethyl or triethyl orthoformate. Amixture containing diethoxymethylacetate and the above compound offormula (X) is heated at 75° to 150° C., preferably from 75° to 125° C.for 30 minutes to 2 hours, preferably from 30 minutes to 11/2 hours.Compound of formula (XI) wherein B is 6-chloropurin-9-yl is recoveredby, e.g., chromatography. When the orthoformate is used, compound offormula (X) and the orthoformate are dissolved in dry toluene containinghydrogen chloride.

When the desired B is an optionally substituted pyrimidine as definedabove, compound of formula (X) wherein R is an(alkoxyethenylcarbonyl)aminocarbonyl is prepared by reacting compound offormula (IX) with an alkoxyacryloylisocyanate such asethoxyacrylolyisocyanate to form the above urea of formula (X). Thealkoxyacryloylisocyanate is prepared by the method described in J.Heterocyclic Chem., 13:1015 (1976). An alkoxyacrylic acid is convertedto its sodium salt by reaction with sodium hydroxide which is thenreacted with thionyl chloride. The chloride is converted to theisocyanate by reaction with a metal cyanate such as silver cyanate. Thechloride in a solvent such as benzene is added to a refluxing solutionof benzene and the metal cyanate. After the addition is complete themixture is heated for 15 minutes to one hour, preferably for 30 minutes,followed by stirring for 1 to 4 hours, preferably for 2 to 3 hours atroom temperature. The resultant solution containing the isocyanate wasadded dropwise to dry dimethylformamide solution of compound of formula(IX) under dry nitrogen at -20° to 0° C., preferably at -15° C. to -5°C. After addition the mixture is allowed to warm to room temperature andstirred at room temperature overnight. Compound of formula (X) isrecovered by recrystallization from, e.g., ether when R isN'-(2-ethoxy-1-methylethenylcarbonyl)aminocarbonyl,alkoxymethacryloylisocyanate is used in the above process.

The following compounds of formula (X) wherein R isN'-(2-ethoxyethenylcarbonyl)aminocarbonyl orN'-(2-ethoxy-1-methylethenylcarbonyl)aminocarbonyl, Z is hydroxy, fluoroor hydrogen and Z' is fluoro or hydrogen may be prepared by the abovemethods:

3-[N'-(2-ethoxyethenecarbonyl)aminocarbonylamino]-4-fluoro-5-benzyloxymethyl-1,2-isopropylidenedioxycyclopentane;

3-[N'-(2-ethoxyethenecarbonyl)aminocarbonylamino]-4,4-difluoro-5-benzyloxymethyl-1,2-isopropylidenedioxycyclopentane;

3-[N'-(2-ethoxyethenecarbonyl)aminocarbonylamino]-4-hydroxy-5-benzyloxymethyl-1,2-isopropylidenedioxycyclopentane;

3-[N'-(2-ethoxyethenecarbonyl)aminocarbonylamino]-4-oxo-5-benzyloxymethyl-1,2-isopropylidenedioxycyclopentane;

3-[N'-(2-ethoxy-1-methylethenecarbonyl)aminocarbonylamino]-4-fluoro-5-benzyloxymethyl-1,2-isopropylidenedioxycyclopentane;

3-[N'-(2-ethoxy-1-methylethenecarbonyl)aminocarbonylamino]-4,4-difluoro-5-benzyloxymethyl-1,2-isopropylidenedioxycyclopentane;

3-[N'-(2-ethoxy-1-methylethenecarbonyl)aminocarbonylamino]-4-hydroxy-5-benzyloxymethyl-1,2-isopropylidenedioxycyclopentane;and

3-[N'-(2-ethoxy-1-methylethenecarbonyl)aminocarbonylamino]-4-oxo-5-benzyloxymethyl-1,2-isopropylidenedioxycyclopentane.

Compound (X) is cyclized in the presence of an acid catalyst such assulfuric acid, toluenesulfonic acid and the like. Compound (X) and theacid catalyst are heated under reflux for 1 to 5 hours, preferably for21/2 to 4 hours. After cooling, the solution is diluted with water andneutralized with a base such as sodium hydroxide. Compound of formula(XI) wherein B is pyrimidinyl is recovered by recrystallization frome.g. cyclohexane.

The following compounds of formula (XI) wherein B is an optionallysubstituted pyrimidinyl group as defined above are prepared by the abovemethods:

3-(2,4-dioxo-5-methylpyrimidin-1-yl)-4-fluoro-5-benzyloxymethyl-1,2-isopropylidenedioxycyclopentane;

3-(2,4-dioxo-5-methylpyrimidin-1-yl)-4,4-difluoro-5-benzyloxymethyl-1,2-isopropylidenedioxycyclopentane;

3-(2,4-dioxo-5-methylpyrimidin-1-yl)-4-hydroxy-5-benzyloxymethyl-1,2-isopropylidenedioxycyclopentane;

3-(2,4-dioxo-5-methylpyrimidin-1-yl)-4-oxo-5-benzyloxymethyl-1,2-isopropylidenedioxycyclopentane;

3-(2,4-dioxopyrimidin-1-yl)-4-fluoro-5-benzyloxymethyl-1,2-isopropylidenedioxycyclopentane;

3-(2,4-dioxopyrimidin-1-yl)-4,4-difluoro-5-benzyloxymethyl-1,2-isopropylidenedioxycyclopentane;

3-(2,4-dioxopyrimidin-1-yl)-4-hydroxy-5-benzyloxymethyl-1,2-isopropylidenedioxycyclopentane;and

3-(2,4-dioxopyrimidin-1-yl)-4-oxo-5-benzyloxymethyl-1,2-isopropylidenedioxycyclopentane.

The benzyl group on compound of formula (XI) wherein B is 6-aminopurinylis removed by transfer hydrogenolysis. An ethanol suspension of compoundof formula (XI) with a catalyst such as palladium hydroxide on carboncontaining cyclohexene, 1,4-cyclohexadiene and the like is refluxed for3 to 12 hours, preferably for 4 to 8 hours. After removal of thecatalyst by filtration compound of formula (XII) is recovered andpurified by, e.g., chromatography.

Compounds of formula (I) wherein A and C are hydroxy are prepared fromcompound of formula (XII) by removal of the isopropylidene group byacidic hydrolysis using, e.g., acetic acid, hydrochloric acid and thelike. Compound of formula (XII) in the acid is heated at 50° C. to 100°C., preferably at 55° to 75° C. for 15 minutes to 11/2 hours, preferablyfor 15 mnutes to 45 minutes. After concentration of the solution,compound of formula (I) is recovered by recrystallization from, e.g.,ethyl acetate-methanol.

When B is 2,4-dioxo-5-fluoropyrimidin-1-yl compound of formula (I) maybe prepared by fluorinating the 2,4-dioxopyrimidin-1-yl ring withtrifluoromethyl hypofluorite or elemental fluorine according to themethod described in J. Med. Chem., 24(9):1083 (1981). To compound offormula (I) wherein B is 2,4-dioxopyrimidin-1-yl in acetic acid isbubbled a fluorine-nitrogen mixture for 5 minutes to 30 minutes,preferably for 10 minutes. The solution is then concentrated to drynessand the compound of formula (I) wherein B is2,4-dioxo-5-fluoropyrimidin-1-yl is recovered by extraction withethanol.

Compound of formula (I) wherein B is 4-amino-2-oxopyrimidin-1-yl may beprepared by the method described in J. Heterocyclic Chem., 17:353(1980). Compound of formula (I) wherein B is 2,4-dioxopyrimidin-1-yl ina solvent such as dimethylformamide is reacted with thionyl chloridewhich replaces one oxo group on the ring by a chloro group. The mixtureis heated under reflux for 4 to 10 hours, preferably for 3 to 8 hours.The chloro compound is recovered by concentration under reducedpressure. The resultant solid dissolved in a solution of ammonia inmethanol is heated in a Parr bomb at 80° to 150° C., preferably at 90°to 110° C. for 12 to 36 hours, preferably for 16 to 24 hours. Compoundof formula (I) wherein B is 4-amino-2-oxopyrimidin-1-yl is recovered byrecrystallization from, e.g., ether-alcohol mixture.

Other 5-substituted pyrimideinediones such as bromo, iodo, alkylamino,hydroxymethyl and the like may be prepared by the methods described inJ. Med. Chem., 26(2):156 (1983). The compounds wherein the 5-position issubstituted by a halovinyl group may be prepared by the method describedin European Pat. No. 104,066.

Using the methods described above the following compounds may beprepared:

3-(2,4-dioxo-5-methylpyrimidin-1-yl)-4-fluoro-5-hydroxymethylcyclopentane-1,2-diol;

3-(2,4-dioxo-5-methylpyrimidin-1-yl)-4,4-difluoro-5-hydroxymethylcyclopentane-1,2-diol;

3-(2,4-dioxo-5-methylpyrimidin-1-yl)-4-hydroxy-5-hydroxymethylcyclopentane-1,2-diol;

3-(2,4-dioxo-5-methylpyrimidin-1-yl)-4-oxo-5-hydroxymethylcyclopentane-1,2-diol;

3-(2,4-dioxopyrimidin-1-yl)-4-fluoro-5-hydroxymethylcyclopentane-1,2-diol;

3-(2,4-dioxopyrimidin-1-yl)-4,4-difluoro-5-hydroxymethylcyclopentane-1,2-diol;

3-(2,4-dioxopyrimidin-1-yl)-4-hydroxy-5-hydroxymethylcyclopentane-1,2-diol;

3-(2,4-dioxopyrimidin-1-yl)-4-oxo-5-hydroxymethylcyclopentane-1,2-diol;

3-(2,4-dioxo-5-fluoropyrimidin-1-yl)-4-fluoro-5-hydroxymethylcyclopentane-1,2-diol;

3-(2,4-dioxo-5-fluoropyrimidin-1-yl)-4,4-difluoro-5-hydroxymethylcyclopentane-1,2-diol;

3-(2,4-dioxo-5-fluoropyrimidin-1-yl)-4-hydroxy-5-hydroxymethylcyclopentane-1,2-diol;

3-(2,4-dioxo-5-fluoropyrimidin-1-yl)-4,4-oxo-5-hydroxymethylcyclopentane-1,2-diol;

3-(4-amino-2-oxopyrimidin-1-yl)-4-fluoro-5-hydroxymethylcyclopentane-1,2-diol;

3-(4-amino-2-oxopyrimidin-1-yl)-4,4-difluoro-5-hydroxymethylcyclopentane-1,2-diol;

3-(4-amino-2-oxopyrimidin-1-yl)-4-hydroxy-5-hydroxymethylcyclopentane-1,2-diol;and

3-(4-amino-2-oxopyrimidin-1-yl)-4-oxo-5-hydroxymethylcyclopentane-1,2-diol.

Compounds of formula (I) wherein A and C are both hydroxy and C is inthe β-position may be prepared by reacting the compound wherein A and Care in the α-position with a silylating reagent by the method describedin Tetrahedron Letters, 157-4 (1980). The silyl protected compound isthen reacted with trifluoromethanesulfonyl chloride followed by reactionwith salts such as sodium acetate by the methods described inTetrahedron Letters, 4341-44 (1978). The acetate group is removed withmethanolic ammonia.

Compounds of formula (I) wherein A is hydroxy and C is hydrogen may beprepared from the above silyl protected compound by reaction with1,1-diimidazolylthiocarbonyl followed by reduction with tributyl tinhydride.

For example, the following compounds may be prepared by the methodsdiscussed above.

3-(2,4-dioxo-5-iodopyrimidin-1-yl)-4-fluoro-5-hydroxymethylcyclopentan-1-ol;

3-(2,4-dioxo-5-iodopyrimidin-1-yl)-4,4-difluoro-5-hydroxymethylcyclopentan-1-ol;

3-(2,4-dioxo-5-iodopyrimidin-1-yl)-4-hydroxy-5-hydroxymethylcyclopentan-1-ol;

3-(2,4-dioxo-5-iodopyrimidin-1-yl)-4-oxo-5-hydroxymethylcyclopentan-1-ol;

3-(2,4-dioxo-5-fluoropyrimidin-1-yl)-4-fluoro-5-hydroxymethylcyclopentan-1-ol;

3-(2,4-dioxo-5-fluoropyrimidin-1-yl)-4,4-difluoro-5-hydroxymethylcyclopentan-1-ol;

3-(2,4-dioxo-5-fluoropyrimidin-1-yl)-4-hydroxy-5-hydroxymethylcyclopentan-1-ol;

3-(2,4-dioxo-5-fluoropyrimidin-1-yl)-4-oxo-5-hydroxymethylcyclopentan-1-ol;

3-(2,4-dioxo-5-trifluoromethylpyrimidin-1-yl)-4-fluoro-5-hydroxymethylcyclopentan-1-ol;

3-(2,4-dioxo-5-trifluoromethylpyrimidin-1-yl)-4,4-difluoro-5-hydroxymethylcyclopentan-1-ol;

3-(2,4-dioxo-5-trifluoromethylpyrimidin-1-yl)-4-hydroxy-5-hydroxymethylcyclopentan-1-ol;

3-(2,4-dioxo-5-trifluoromethylpyrimidin-1-yl)-4-oxo-5-hydroxymethylcyclopentan-1-ol;

3-(2,4-dioxo-5-(2-bromovinyl)pyrimidin-1-yl)-4-fluoro-5-hydroxymethylcyclopentan-1-ol;

3-(2,4-dioxo-5-(2-bromovinyl)pyrimidin-1-yl)-4,4-difluoro-5-hydroxymethylcyclopentan-1-ol;

3-(2,4-dioxo-5-(2-bromovinyl)pyrimidin-1-yl)-4-hydroxy-5-hydroxymethylcyclopentan-1-ol;

3-(2,4-dioxo-5-(2-bromovinyl)pyrimidin-1-yl)-4-oxo-5-hydroxymethylcyclopentan-1-ol;

3-(2,4-dioxo-5-(2-iodovinyl)pyrimidin-1-yl)-4-fluoro-5-hydroxymethylcyclopentan-1-ol;

3-(2,4-dioxo-5-(2-iodovinyl)pyrimidin-1-yl)-4,4-difluoro-5-hydroxymethylcyclopentan-1-ol;

3-(2,4-dioxo-5-(2-iodovinyl)pyrimidin-1-yl)-4-hydroxy-5-hydroxymethylcyclopentan-1-ol;and

3-(2,4-dioxo-5-(2-iodovinyl)pyrimidin-1-yl)-4-oxo-5-hydroxymethylcyclopentan-1-ol.

Compounds of formula (I) wherein B is2,4-dioxo-5-trifluoromethylpyrimidin-1-yl or4-amino-2-oxo-5-trifluoromethylpyrimidin-1-yl may be prepared byreacting compound of formula (IX) with trifluoroacrylonitrile which isprepared by the method described in J. Med. Chem., 7(1):1-5 (1964). Theresulting compound is reacted with cyanic acid to form compound offormula (X) wherein R is 1-(2-cyanoethyl)-1-trifluoromethylaminocarbonylas is described in J. Heterocyclic Chem., 527-535 (1970). This compoundis cyclized with a base such as sodium methoxide to form a compound offormula (XI) followed by reaction with bromine. The bromine compound isdehydrobromenated using a base such as sodium hydroxide in methanol. Thebenzyl group and the isopropylidene are removed by the methods describedabove. Compound of formula (I) wherein B is4-amino-2-oxo-5-trifluoromethylpyrmidin-1-yl is converted to thecompound of formula (I) wherein B is2,4-dioxo-5-trifluoromethylpyrimidin-1-yl by treatment with nitrousacid.

The compounds of formula (XIII) are prepared from the compounds offormula (I) wherein B is a substituted pyrimidinyl and the hydroxygroups in the 1 and 2 positions of the cyclopentyl ring are in the downposition by the method described in U.S. Pat. No. 3,709,874. The abovecompound of formula (I) is reacted with an α-acyloxy acid halide such as2-acetyloxy-3- methylbutanoyl chloride in an inert organic solvent at 0°to 150° C. for about 5 minutes to 10 hours, preferably at 20° C. to 100°C. for 5 minutes to one hour. The compound of formula (XIV) is recoveredby, e.g., chromatography. The α-acyloxy acid halide is prepared byreacting an α-hydroxy acid with an acid chloride. The resultingα-acyloxy acid is then treated with thionyl chloride or oxalyl chlorideto form the α-acyloxy acid chloride.

The following compounds, for example, may be prepared by the abovemethod:

    ______________________________________                                        X         Y             Z         Z'                                          ______________________________________                                        oxygen    iodo          fluoro    hydrogen                                    oxygen    iodo          fluoro    fluoro                                      oxygen    methyl        fluoro    hydrogen                                    oxygen    methyl        fluoro    fluoro                                      oxygen    trifluoromethyl                                                                             fluoro    hydrogen                                    oxygen    trifluoromethyl                                                                             fluoro    fluoro                                      imino     iodo          fluoro    hydrogen                                    imino     iodo          fluoro    fluoro                                      ______________________________________                                    

The compound of formula (XIII) not only possesses antiviral activity butis also useful as an intermediate for the preparation of the compound offormula (I) wherein B is a substituted pyrimidinyl and the hydroxy groupat position-1 is in the down position and the hydroxy group atposition-2 is in the up position by treating compound of formula (XIII)with a base such as sodium hydroxide.

Another method for preparing the compounds of the invention is byreacting the compound of formula (VI) with a purine derivative. Forexample, for compounds of formula (I) wherein B is guanine, compound offormula (VI) in a solvent such as dimethylformamide is reacted with thesodium salt of guanine.

Compounds of formula (I) exist as optical isomers. The compounds may beprepared as their racemic mixture or may be separated into their opticalisomers by various methods. One such method is by resolving the racemicmixture of the intermediate of formula (VIII) and then reacting eachisomer as described above to prepare optical isomers of compound offormula (I).

Racemic compound of formula (VIII) is reacted with an optically activeacid choride such as 6-methoxynaphth-2-yl-2-propanoyl chloride in asolvent such as dichloromethane containing pyridine. The solution isstirred for 2 to 8 hours, preferably for 3 to 6 hours, at roomtemperature. The diasteromers of compound of formula (VIII) areseparated by chromatography on silica gel. The optical isomers offormula (VIII) is prepared by basic hydrolysis. The diastereoisomer in asolvent such as tetrahydrofuran and a base such as sodium hydroxide isheated at reflux for 2 to 12 hours, preferably for 2 to 8 hours. Thesolution is evaporated to dryness. The optical isomers of formula (VIII)is recovered by chromatography.

The following examples are illustrative of the methods and compositionsof the present invention. They should not be construed as limitativethereof in any manner.

PREPARATION I [Preparation of Compound of Formula (V)]

Benzyl chloromethyl ether (208 mL) was added dropwise over 30 minutes toa mechanically stirred suspension of thallium cyclopentadiene (475 g) inether (450 mL). The resulting suspension was mechanically stirred at-20° C. for an additional 18 hours and then filtered with the filtrateflask precooled to -20° C. The filtrate was evaporated at 0° C./l Torrto give the alkylated cyclopentadiene as a clear oil. The oil wasdissolved in cold (-20° C.) methanol, and transferred to a -5° C.solution of thiourea (126 g), sodium acetate (2.8 g) and Rose Bengal(2-8 g) in methanol (5 gal, saturated with oxygen). The solution wasirradiated at -5° C. for 9 hours with a 400 watt mercury immersion lampwith continuous bubbling of oxygen into the solution. The lamp wascooled with a 0° C. solution of aqueous Na₂ Cr₂ O₇. The resultingsolution was evaporated by a rotary evaporator to a dark brown oil whichwas dissolved in ethyl acetate, washed with water and evaporated to alight brown oil. The oil was chromatographed over silica gel to give 197g of 2β-benzyloxymethyl-1α,3α-dihydroxycyclopent-4-ene, m.p. 47°-48° C.

PREPARATION II [Preparation of Compound of Formula (VI)]

A solution of 2β-benzyloxymethyl-1α,3α-dihydroxycyclpent-4-ene (0.22 g)and m-chloroperbenzoic acid (0.18 g) in dichloromethane (10 ml) wasstirred for 36 hours at room temperature. After filtration, the filtratewas concentrated using a rotary evaporator and chromatographed on silicagel eluting with ethyl acetate-hexane (8:2) to obtain 0.18 g of thecolorless crystals of2β-benzyloxymethyl-1α,3α-dihydroxy-4α,5α-epoxycyclopropane, m.p.170°-171° C.

PREPARATION III [Preparation of Compound of Formula (VII)]

To a stirred solution of2β-benzyloxymethyl-1α,3α-dihydroxy-4α,5α-epoxycyclopentane (0.472 g) indry dimethylformamide (20 ml) was added sodium azide (0.910 g). Themixture was maintained at 100° C. on an oil bath for 12 hours. Thedimethylformamide was evaporated under vacuum and the concentrate waspartitioned between ethyl acetate-water (1:1). The ethyl acetate layerwas concentrated after drying (Na₂ SO₄) to yield a red oil (0.44 g). Theoil was purified on a silica gel column eluting with ethylacetate-hexane (1:1) to yield 0.35 g of the pure5β-benzyloxymethyl-1α,2α,4α-trihydroxy-3β-azidocyclopentane as acolorless liquid.

¹³ C NMR (75.453 MHz, CDCl₃) 137.73, 128.57, 127.95, 127.74 (phenyl),75.05 (C-3), 74.20 (C-4), 73.55 (benzylic), 71.97 (C-2), 71.68 (C-1),70.21 (C-6), 51.81 (C-5).

PREPARATION IV [Preparation of Compound of Formula (VIII)]

To a stirred solution of the azido triol from Preparation III (0.558 g)and 2,2-dimethoxypropane (1 mL) in dry acetone (10 mL) was added 70%perchloric acid (0.1 mL). The resulting solution was stirred for 45minutes at room temperature followed by the dropwise addition ofammonium hydroxide to neutralize the solution. The solvents were removedat the rotary evaporator. The crude concentrate was dissolved in ethylacetate, washed twice with water and brine. The organic layer wasconcentrated at the rotary evaporator to yield a dark brown liquid (0.62g). The brown liquid was purified by column chromatography [silica geleluting with hexane-ethyl acetate (8:2)] to yield 0.54 g of3β-azido-4α-hydroxy-5β-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentaneas a colorless liquid.

¹³ C NMR (75.453 MHz, CDCl₃) 137.76, 128.57, 127.96, 127.76 (phenyl),113.12 (OCO), 81.30 (C-2), 77.87 (C-1, C-4), 73.58 (benzylic), 72.23(C-3), 69.54 (C-6), 50.28 (C-5), 27.25 (CH₃), 24.86 (CH₃).

PREPARATION V (Preparation of Compound of Formula (IX) wherein Z ishydroxy and Z' is hydrogen)

Hydrogen gas was added to a solution of3β-azido-4α-hydroxy-5β-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentane(0.31 g) and palladium on calcium carbonate (0.75 g) in methanol (15 mL)from a rubber balloon attached to the flask. After the solution wasstirred for 12 hours, the catalyst was filtered off and washed with hotmethanol (2×25 mL). The washings were combined with the filtrate and theresulting solution was concentrated. The concentrate was chromatographedover silica gel eluting with ethyl acetate. After the solvent wasremoved by rotary evaporator, light yellow crystals (0.26 g) of3β-amino-4α-hydroxy-5β-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentanewere obtained. Recrystallization with hexane-ethyl acetate gave pure3β-amino-4α-hydroxy-5β-benzyloxymethyl-1α,2α-isopropylidinedioxycyclopentane,m.p. 106°-107° C.

PREPARATION VI (Preparation of Compound of Formula (X) wherein Z ishydroxy, Z' is hydrogen and R is 5-amino-6-chloro-0-pyrimidin-4-yl)

A solution of3β-amino-4α-hydroxy-5β-benzyloxymethyl-1α,2αisopropylidenedioxycyclopentane(0.293 g), pyridine (0.08 g) in N-methyl-2-pyrrolidone (25 mL) and5-amino-4,6-dichloropyrimidine (0.164 g) was stirred at 180° C. for 12hours. The solvent was removed by rotary evaporator and the concentratewas dissolved in ethyl acetate (25 mL). The ethyl acetate solution waswashed with water (25 mL), dried (Na₂ SO₄) and concentrated by a rotaryevaporator to yield 0.44 g of a brown oil. This oil was chromatographedover silica gel eluting with ethyl acetate-hexane (1:1) to yield 0.285 gof3β-(5-amino-6-chloropyrimidin-4-yl)amino-4-α-hydroxy-5β-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentane,as light yellow crystals, m.p. 108°-109° C.

PREPARATION VII (Preparation of Compound of Formula (XI) wherein Z ishydroxy, Z' is hydrogen and B is 6-chloropurin-9-yl)

3β-(5-Amino-6-chloropyrimidin-3-yl)amino-4α-hydroxy-5β-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentane-1α,2.alpha.-acetonide(0.210 g) in diethoxymethylacetate (5 mL) was heated at 100° C. for 1hour under nitrogen atmosphere. After concentration of the solution by arotary evaporator, toluene and p-toluenesulphonic acid (2 crystals) wereadded and the solution was stirred at room temperature for 1 hour. Afterremoval of the solvent by a rotary evaporator, the crude concentrate waschromatographed over silica gel eluting with methylene chloride-methanol(9.5:0.5) to give 0.215 g of3β-(6-chloropurin-9-yl)-4α-hydroxy-5β-benzyloxymethyl-1.alpha.,2α-isopropylidenedioxycyclopentane which after recrystallization from hexane-ethyl acetate(8:2) gave a colorless crystalline solid, m.p. 190°-191° C.

PREPARATION VIII (Preparation of Compound of Formula (XI) wherein Z ishydroxy, Z' is hydrogen and B is 6-aminopurin-9-yl)

A solution of3β-(6-chloropurin-9-yl)-4α-hydroxy-5β-benzyloxymethyl-1.alpha.,2α-isopropylidenedioxycyclopentane(0.215 g) in anhydrous methanolic ammonia (10 mL) was heated for 48hours at 60° C. in a lightly sealed flask. The solvent was removed by arotary evaporator and the resultant white solid was recrystallized fromethyl acetate-methanol (9:1).3β-(6-Aminopurin-9-yl)-4α-hydroxy-5β-benzyloxymethyl-1.alpha.,2α-isopropylidenedioxycyclopentane(0.15 g) was obtained as a colorless solid, m.p. 236°-237° C.

PREPARATION IX (Preparation of Compound of Formula (XII) wherein Z ishydroxy, Z' is hydrogen and B is 6-aminopurin-9-yl)

A solution of3β-(6-aminopurin-9-yl)-4α-hydroxy-5β-benzyloxymethyl-1.alpha.,2α-isopropylidenedioxycyclopentane(8 mg) and cyclohexene (1 mL) in ethanol (2 mL) containing palladiumhydroxide on carbon (3 mg) was refluxed for 6 hours. The catalyst wasremoved by filtration and washed with hot ethanol (2×10 mL). Thewashings were combined with the filtrate and concentrated by a rotaryevaporator. The concentrated filtrate was purified by silica gelchromatography eluting with methylene chloride-methanol (8:2).3β-(6-Aminopurin-9-yl)-4α-hydroxy-5β-hydroxymethyl-1.alpha.,2α-isopropylidenedioxycyclopentane(64 mg) as colorless crystals were obtained, m.p. 238°-239° C.

PREPARATION X

To a solution of3β-azido-4α-hydroxy-5β-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentane(0.40 g) and pyridine (0.12 g) in dichloromethane (10 mL) was addedtrifluoromethanesulfonic anhydride (0.31 g) in dichloromethane (2 ml).The resulting solution was stirred at room temperature under nitrogenatmosphere for 1 hour. The solution was diluted with 20 mL ofdichloromethane, washed with 20 mL of 0.1N NaHCO₃ and water. From thedichloromethane layer was obtained3β-azido-4α-trifluoromethanesulfoxy-5β-benzyloxymethyl-1.alpha.,2α-isopropylidenedioxycyclopentane(0.50 g).

PREPARATION XI (Preparation of Compound of Formula (IX) wherein Z isfluoro and Z' is hydrogen)

A. A solution containing3β-azido-4α-trifluoromethanesulfonyloxy-5β-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentane(0.30 g) from preparation (X) and tris(dimethylamino)sulfoniumdifluorotrimethylsilicate (TASF) (0.22 g) in dry tetrahydrofuran (5 mL)was stirred under nitrogen atmosphere for 12 hours under reflux. Thesolution was diluted with ethyl acetate (20 mL), washed with water anddried with Na₂ SO₄. The ethyl acetate layer was concentrated using arotary evaporator and chromatographed over silica gel eluting withhexane-ethyl acetate (8:2).3β-Azido-4β-fluoro-5β-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentanewas isolated as a clear liquid (0.20 g).

¹ H-NMR (CHCl₃) 7.35-7.25 (m, 5H, phenyl), 5-20 (t, J=Hz, 3 Hz, 52 Hz,1H, H-4), 4.68 (t, J=6 Hz, 1H, H-2), 4.56 (S, 2H, benzylic), 4.48 (t,J=66 Hz, 1H, H-1), 3.75 (m, 1H, H-3), 3.66 (d, J=4 Hz, 2H, H-6) and 2.50(m, 1H, H-5).

B. To a solution containing3β-azido-4β-fluoro-5β-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentane(0.09 g) in methanol (5 mL) was added palladium on calcium carbonate(0.009 g) and the suspension was stirred under positive hydrogenpressure for 6 hours. After removal of the catalyst by filtration, thesolution was concentrated by rotary evaporator and chromatographed oversilica gel eluting with methylenechloride-methanol (9.8:02) to obtain3β-amino-4β-fluoro-5β-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentane was obtained as a viscous oil,

¹ H NMR (300 MHz, CDCl₃) 7.2-7.4 (m, SH, phenyl), 5.0 (ddd J=3.1, 3.1and 53 Hz, 1H, H-4), 4.56 (s, 2H, benzylic), 4.43 (dd J=7.2, 7.2 Hz, 1H,H-3'), 4.35 (dd J=7.2 Hz, 1H, H-2'), 3.66 (d, J=7.9 Hz, 2H, H-6), 3.30(ddd, J=5.6, 5.6 and 29.9 Hz, 1H, H-3), 2.60-2.35 (m, 1H, H-5), 1.54(broad singlet, 2H, NH₂, disappears on D₂ O), 1.50 and 1.30 (2×s, 3Heach, 2×CH₃).

PREPARATION XII (Preparation of Compound of Formula (X) wherein Z isfluoro, Z' is hydrogen and R is 5-amino-6-chloropyrimidin-4-yl)

A solution containing3β-amino-4β-fluoro-5β-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentane(0.6 g), 5-amino-4,6-dichloropyrimidine (0.66 g) and triethylamine (1.60g) in n-butanol (10 mL) was refluxed for 48 hours under nitrogenatmosphere. After cooling to room temperature, the triethylaminehydrochloride was removed by filtration. The filtrate was concentratedusing a rotary evaporator and the concentrated filtrate partitionedbetween ethyl acetate and water. The ethyl acetate layer waschromatographed over silica gel eluting with hexane-ethyl acetate (6:4).After evaporation of the solvent3β-(5-amino-6-chloropyrimidin-4-yl)amino-4β-fluoro-5β-benzyloxymethyl)-1α,2α-isopropylidenedioxycyclopentane(0.55 g) was obtained as colorless crystals, m.p. 172°-173° C.

PREPARATION XIII (Preparation of Compound of Formula (XI) wherein Z isfluoro, Z' is hydrogen and B is 6-chloropurin-9-yl)

A solution of3β-(5-amino-6-chloropyrimidin-4-yl)-amino-4β-fluoro-5β-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentane(0.42 g) in diethoxymethylacetate (4 mL) was heated at 100° C. on as oilbath for 12 hours. The solution was concentrated by a rotary evaporatorand chromatographed over silica gel, eluting with hexane-ethyl acetate(8:2). After evaporation of the solvent3β-(6-chloropurin-9-yl)-4β-fluoro-5β-benzyloxymethyl-1.alpha.,2α-isopropylidenedioxycyclopentane(0.35 g) as a light yellow gummy solid.

¹ H NMR (300 MHz, CDCl₃) 8.77 (s, 1H, H-2), 8.34 (d, J=2.3 Hz, 1H, H-8),7.33-7.26 (m, 5H, phenyl), 5.23 (ddd, J=3.1, 3.1 and 46.12 Hz),5.10-5.30 (M, 2H, H-3* and H-2*) 4.66 (dd, J=7.5 Hz, 1H, H-1*), 4.59 (S,2H, benzylic), 3.75 (d, J=8.0 Hz, 2H, H-6*) 3.90-3.70 (M, 1H, H-5*),1.59 and 1.35 (2×S, 3H each, 2×CH₃).

PREPARATION XIV (Preparation of Compound of Formula (XI) wherein Z isfluoro, Z' is hydrogen and B is 6-aminopurin-9-yl)

A solution of3β-(6-chloropurin-9-yl)-4β-fluoro-5β-benzyloxymethyl-1.alpha.,2α-isopropylidenedioxycyclopentane(2.0 g) in methanolic ammonia (20 mL) in a bomb reactor was kept at 90°C. for 6 hours. The solution was concentrated by a rotary evaporator andthe resulting solid was dissolved in methanol and chromatographed oversilica gel eluting with methylene chloride-methanol (9.9:0.1).3β-(6-Aminopurin-9-yl)-4β-fluoro-5β-benzyloxymethyl-1.alpha.,2α-isopropylidenedioxycyclopentane(1.13 g) was obtained as a colorless solid, m.p. 178°-179° C.

PREPARATION XV (Preparation of Compound of Formula (XII) wherein Z isfluoro, Z' is hydrogen and B is 6-aminopurin-9-yl)

A solution of3β-(6-aminopurin-9-yl)-4β-fluoro-5β-benzyloxymethyl-1.alpha.,2α-isopropylidenedioxycyclopentane(0.8 g), palladium hydroxide on carbon (0.08 g) and cyclohexane (6 mL)in ethanol (10 mL) was refluxed for 48 hours. The catalyst was filteredoff and the filtrate was concentrated by a rotary evaporator. Theconcentrated filtrate was chromatographed over silica gel eluting withmethylene chloride-methanol (9.5:0.6). After recrystallization fromhexane-ethylacetate3β-(6-aminopurin-9-yl)-4β-fluoro-5β-hydroxymethyl-1α,2α-isopropylidenedioxycyclopentane(0.50 g) was obtained as colorless crystals, m.p. 132°-133° C.

PREPARATION XVI (Preparation of Compound of Formula (VIII) wherein the4-hydroxy is in the up (β) position)

A solution containing3β-azido-4α-trifluoromethanesulfonoxy-5β-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentanefrom Preparation (X) (0.5 g) and lithium fluoride (0.52 g) indimethylsulfoxide (5 mL) was stirred for 4 hours at room temperature.The reaction mixture was diluted with ethylacetate (25 mL) and washedwith water (2×15 mL). The ethyl acetate layer was chromatographed oversilica gel eluting with hexane-ethyl acetate (8:2) and3β-azido-4-β-hydroxy-5β-benzyloxymethyl-1α,2α-isopropylidenedioxy (0.30g) was obtained as a clear oil.

PREPARATION XVII [Preparation of Optically Active Compounds of Formula(VIII)]

A. To a solution of racemic3β-azido-4α-hydroxy-5β-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentane(0.32 g) in dichloromethane (10 mL) containing pyridine (1 mL) was addedthe 6-methoxynaphth-2-yl-2-propanoyl chloride in 3 mL ofdichloromethane. The resulting solution was stirred for 4 hours at roomtemperature and then diluted with 40 mL of dichloromethane. Thissolution was washed with 0.1N NaHCO₃ (2×20 mL), water (10 mL) and brine(10 mL). The dichloromethane layer was separated, concentrated and dried(Na₂ SO₄). The resulting oil was chromatographed over silica gel elutingwith hexane-toluene-ethyl acetate (8.5:1.0:0.5) and each of thediasteromers of the ester was obtained as a light yellow oil (0.211 g).

Diasteromer-1 [α]_(D) ²⁵ 54.6° (C CHCl₃)

Diasteromer-2 [α]_(D) ²⁵ -31.8° (C CHCl₃)

B. A solution of diasteromer 2 from Part A (5.0 g) and sodium hydroxide(0.40 g) in tetrahydrofuran (50 mL) was heated at reflux for 4 hours.The solution was evaporated to dryness using a rotary evaporator. Theresidue was dissolved in ethyl acetate, washed with saturated aqueousNaHCO₃, dried over Na₂ SO₄ and evaporated to dryness. The residue wasdissolved in ethyl acetate and purified by chromatography over silicagel eluting with ethyl acetate-hexane (1:9) to give 2.54 g of(-)-3β-azido-4α-hydroxy-5β-benzyloxymethyl-1α,2.alpha.-isopropylidenedioxycyclopentaneas a clear oil.

[α]_(D) ²⁵ -26.0° (C 0.3, CHCl₃)

Similarly,(+)-3β-azido-4α-hydroxy-5β-benzyloxymethyl-1α,2.alpha.-isopropylidenedioxycyclopentaneusing the above procedure was obtained from diasteromer-1.

[α]_(D) ²⁵ 26.1° (C 0.28, CHCl₃)

PREPARATION XVIII

A solution of3β-(6-aminopurin-9-yl)-4α-hydroxy-5β-benzyloxymethyl-1.alpha.,2α-isopropylidenedioxycyclopentane(35 mg) and 1,1-diimidazolylthiocarbonyl (27 mg) in dimethylformamide(0.2 mL) was heated at 75° C. for 3 hours. The solution was concentratedby a rotary evaporator and the residue was chromatographed over silicagel eluting with methanol-methylene chloride (1:14) to yield 27.4 mg of3β-(6-aminopurin-9-yl)-4α-(1-imidazolylthiocarbonyloxy)-5β-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentaneas a white solid, m.p. 163°-165° C.

PREPARATION XIX (Preparation of Compound of Formula (IX) wherein Z andZ' are both hydrogen)

A. A solution of(-)-3β-azido-4α-hydroxy-5β-benzyloxymethyl-1α,2.alpha.-isopropylidenedioxycyclopentane(1.76 g), trifluoromethanesulfonic anhydride (1.68 g) and pyridine (0.56g) in dichloromethane (15 mL) was kept at room temperature for 1 hour.The solution was washed with water and saturated aqueous NaHCO₃, driedover Na₂ SO₄ and evaporated by a rotary evaporator to give thetrifluoromethanesulfonate as a brown oil. A solution of the residue andlithium iodide (0.9 g) in dimethylformamide (20 mL) was kept at roomtemperature for 1 hour. The solution was then diluted with ethylacetate, washed with water, dried over Na₂ SO₄ and evaporated todryness. The residue was purified by chromatography to give 1.65 g of(-)-3β-azido-4β-iodo-5β-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentaneas a yellow oil. [α]_(D) ²⁵ -33.6° C. (C 0.3, CHCl₃)

Similarly, using the above procedure(+)-3β-azido-4α-iodo-5β-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentanewas obtained from the (+)-azido hydroxy acetonide [α]_(D) ²⁵ 33.6° C. (C0.3, CHCl₃).

B. A mixture of(-)-3β-azido-4β-iodo-5β-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentaneand 10% palladium on carbon (0.15 g) in methanol (25 mL) was shaken on aParr apparatus under 20 psi of hydrogen at room temperature for 6 hoursand then filtered through Celite. The filtrate was evaporated to drynessusing a rotary evaporator and the residue was dissolved in methanol andchromatographed over silica gel eluting with methanol-methylene chloride(0.5:9.5) to give 0.78 g of(-)-3β-amino-5β-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentane asa yellow oil.

[α]_(D) ²⁵ -2.9° (C 0.8, CHCl₃)

Similarly, using the above procedure(+)-3-amino-5-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentane wasobtained from the (+)-azido iodo acetonide.

[α]_(D) ²⁵ 2.80° (C 0.59, CHCl₃)

PREPARATION XX

A solution of(-)-3β-amino-5β-benzyloxymethyl-1α,2α-isopropylidenedioxycyclopentane(0.60 g) in 80% aqueous acetic acid (5 mL) was heated at 80° C. for 1hour and then evaporated to dryness using a rotary evaporator. Themagnetically stirred solution of the residue in ammonia (15 mL) at -78°C. was treated with sodium and then quenched with ammonium chloride. Thesolution was then evaporated to dryness. The residue dissolved inion-free water was purified on a cation exchange resin (Dowex AG 50W-x8, H+ form) eluting with 0.07M ammonium hydroxide to give 0.20 g of(-)-3β-amino-5β-hydroxymethylcyclopentane-1α,2α-diol as a clear oil.

[α]_(D) ²⁵ -10.3° (C 0.3, CHCl₃)

Similarly, using the above procedure(+)-3β-amino-5β-hydroxymethylcyclopentane-1α,2α-diol was obtained fromthe (+) amino acetonide.

[α]_(D) ²⁵ 10.3° (C 0.32, H₂ O)

EXAMPLE 1 (Preparation of Compound of Formula (I) wherein Z is hydroxy,Z' is hydrogen and B is 6-aminopurin-9-yl)

3β-(6-Aminopurin-9-yl)-4α-hydroxy-5β-hydroxymethyl-1α,2α-isopropylidenedioxycyclopentane(0.16 g) was heated at 65° C. in 70% acetic acid for 30 minutes andconcentrated by rotary evaporator. The resulting colorless crystals wererecrystallized from ethyl acetate-methanol to yield 0.12 g of3β-(6-aminopurin-9-yl)-5β-hydroxymethylcyclopentane-1α,2.alpha.,4α-triol,m.p, 244°-245° C.

EXAMPLE 2 (Preparation of Compound of Formula (I) wherein Z is fluoro,Z' is hydrogen and B is 6-aminopurin-9-yl)

A solution of 100 mg of3β-(6-aminopurin-9-yl)-4β-fluoro-5β-hydroxymethyl-1α,2α-isopropylidenedioxycyclopentanein 10% aqueous hydrochloric acid (3 mL) was warmed to 70° C. for a fewminutes and the solvents were then removed by a rotary evaporator. Theresulting colorless gelatinous material was triturated with ammoniumhydroxide and concentrated. The colorless solid was crystallized fromhot water to give3β-(6-aminopurin-9-yl)-4β-fluoro-5β-hydroxymethylcyclopentane-1α,2α-diol(0.08 g) colorless crystals, m.p. 280°-281° C.

EXAMPLE 3

A solution of N⁶ -benzoyladenine (0.35 g) and sodium hydride (0.035 g)in anhydrous dimethylformamide (5 ml) was kept at 100° C. for 45minutes. To this solution was added5β-benzyloxymethyl-1α,2α-dihydroxy-4α,5α-epoxy cyclopentane and theresulting solution was stirred at 100° C. for 12 hours. The solvent wasremoved at the rotary evaporator and the resulting solid mass waspartitioned between water and n-butyl alcohol-methylene chloride (1:9).The organic layer was separated, dried with anhydrous sodium sulphateand concentrated to yield 0.12 g of a red brown viscous liquid which onpreparative plate silica gel chromatography (methylene chloride-methanol(9:1) as eluant), yielded3β-(6-aminopurin-9-yl)-4α-hydroxy-5β-benzyloxymethylcyclopentane-1α,2α-diol(0.03 g) as a yellow solid, mp. 165°-6° C.

The benzyl group is removed by reduction with palladium hydroxide oncarbon to form3β-(6-aminopurin-9-yl)-4α-hydroxy-5β-hydroxymethylcyclopentane-1α,2α-diol.

Similarly, using the above procedure3β-(2-amino-6-hydroxypurin-9-yl)-4α-hydroxy-5β-hydroxymethylcyclopentane-1α,2α-diolis prepared.

EXAMPLE 4

The following example illustrates the preparation of representativepharmaceutical formulations containing an active compound of Formula (I)or compounds of formula (XIII).

    ______________________________________                                        A. Topical Formulation                                                        ______________________________________                                        Active compound          0.2-2  g                                             Span 60                  2      g                                             Tween 60                 2      g                                             Mineral oil              5      g                                             Petrolatum               10     g                                             Methyl paraben           0.15   g                                             Propyl paraben           0.05   g                                             BHA (butylated hydroxy anisole)                                                                        0.01   g                                             Water qs                 100    ml                                            ______________________________________                                    

All of the above ingredients, except water, are combined and heated at60° C. with stirring. A sufficient quantity of water at 60° C. is thenadded with vigorous stirring to provide 100 g of the cream formulationwhich is then cooled to room temperature.

The following formulation is useful for intraperitoneal andintramuscular injection.

    ______________________________________                                        B. IP and IM Formulation                                                      ______________________________________                                        Active compound        0.5    g                                               Propylene glycol       20     g                                               Polyethylene glycol    20     g                                               Tween 80               1      g                                               0.9% Saline solution qs                                                                              100    ml                                              ______________________________________                                    

The active compound is dissolved in propylene glycol, polyethyleneglycol 400 and Tween 80. A sufficient quantity of 0.9% saline solutionis then added with stirring to provide 100 ml of the I.P or I.M solutionwhich is filtered through a 0.2 micron membrane filter and packagedunder sterile conditions.

The following formulation is useful for intravenous injection.

    ______________________________________                                        C. I.V. Formulation                                                           ______________________________________                                        Active compound        0.1    g                                               Polysorbate 80         0.1    g                                               Propylene glycal or    3.0    g                                               polyethylene glycol 400                                                       Water qs               100    ml                                              ______________________________________                                    

The active compound is added to a solution of polysorbate 80 andpropylene glycol or polyethylene glycol 400 in 20 ml of water and mixed.The resulting solution is diluted with water to 100 ml and filteredthrough the appropriate 0.2 micron membrane filter.

    ______________________________________                                        D. Tablet Formulation                                                                          Parts by weight                                              ______________________________________                                        Active compound    200                                                        Magnesium stearate  3                                                         Starch              30                                                        Lactose            116                                                        PVP (polyvinylpyrrolidone)                                                                        3                                                         ______________________________________                                    

The above ingredients are combined and granulated using methanol as thesolvent. The formulation is then dried and formed into tablets(containing 200 mg of active compound) with an appropriate tablettingmachine.

EXAMPLE 5

The exceptional antiviral activity of the compound of the invention isillustrated by the following assay procedures:

The Herpes simplex virus 2 strain G for infection is prepared in HEp-2cell cultures. Virus is adsorbed for 1 hour, fresh media is placed onthe cells, and they are incubated at 35° C. until all cells wereinfected. The cell suspension is frozen at -70° C., thawed, andcentrifuged to remove cell debris. The supernatant fluid is aliquotedand stored frozen at -70° C. until use. A 10⁶.7 dilution of thesupernatant fluid produces a 50% cell culture infective dose (CCID₅₀) inHEp-2 cells and a 10³.7 dilution produces a 50% lethal challenge (LC₅₀)in mice.

Groups of 20 Swiss Webster female mice (15-17 gm), are challenged byintraperitoneal route using 0.2 ml of EMEM containing 10 LC₅₀ /mouse ofvirus. Mice challenged with 10⁰.5 more or less virus than the 10 LD₅₀challenge serves as a virulence control to assure the model is workingproperly.

Treatment with test compounds begins 6 hours post-challenge. The mice,divided into groups of 20, are administered the compounds in saline s.c.at 5 mg/kg, 10 mg/kg and 20 mg/kg. One group of 20 mice is used as acontrol group and administered saline s.c. The treatment is repeated at24, 48, 72 and 96 hours post-challenge.

Compounds of the instant invention show antiviral activity in the abovetest.

What is claimed is:
 1. A compound of the formula ##STR8## wherein A ishydroxy; andC is hydrogen or hydroxy; B is a heterocyclic ring selectedfrom the group consisting of 2-amino-6-hydroxypurin-9-yl,6-aminopurin-9-yl, 2,4-dioxopyrimidin-1-yl optionally substituted at the5-position by fluoro, methyl, iodo, trifluoromethyl, 2-bromovinyl,2-chlorovinyl or 2-iodovinyl, and 4-amino-2-oxopyrimidin-1-yl optionallysubstituted at position-5 by iodo or trifluoromethyl; Z is hydrogen andZ' is hydroxy or fluoro; or Z and Z' are both fluoro; or Z together withZ' is oxo; and the wavy line indicates that the group may be above orbelow the plane of the ring; and the pharmaceutically acceptable acidaddition salts thereof.
 2. A compound of claim 1 wherein A and C areboth hydroxy.
 3. The compound of claim 2 which is3β-[2,4-dioxo-5-(2-bromovinyl)pyrimidin-1-yl]-4α-hydroxy-5.beta.-hydroxymethylcyclopentane-1,2-diol.4. The compound of claim 2 which is3β-[2,4-dioxo-5-(2-bromovinyl)pyrimidin-1-yl]-4β-hydroxy-5β-hydroxymethylcyclopentane-1,2-diol.5. The compound of claim 2 which is3β-[2,4-dioxo-5-(2-bromovinyl)pyrimidin-1-yl]-4α-fluoro-5β-hydroxymethylcyclopentane-1,2-diol.6. The compound of claim 2 which is3β-[2,4-dioxo-5-(2-bromovinyl)pyrimidin-1-yl]-4β-fluoro-5β-hydroxymethylcyclopentane-1,2-diol.7. The compound of claim 2 which is3β-[2,4-dioxo-5-(2-bromovinyl)pyrimidin-1-yl]-4α,4β-difluoro-5β-hydroxymethylcyclopentane-1,2-diol.8. The compound of claim 2 which is3β-(2,4-dioxo-5-trifluoromethylpyrimidin-1-yl)-4α-hydroxy-5.beta.-hydroxymethylcyclopentane-1,2-diol.9. The compound of claim 2 which is3β-(2,4-dioxo-5-trifluoromethylpyrimidin-1-yl)-4β-hydroxy-5.beta.-hydroxymethylcyclopentane-1,2-diol.10. The compound of claim 2 which is3β-(2,4-dioxo-5-trifluoromethylpyrimidin-1-yl)-4α-fluoro-5.beta.-hydroxymethylcyclopentane-1,2-diol.11. The compound of claim 2 which is3β-(2,4-dioxo-5-trifluoromethylpyrimidin-1-yl)-4β-fluoro-5β-hydroxymethylcyclopentane-1,2-diol.12. The compound of claim 2 which is3β-(2,4-dioxo-5-trifluoromethylpyrimidin-1-yl)-4α,4β-difluoro-5β-hydroxymethylcyclopentane-1,2-diol.13. The compound of claim 2 which is3β-(2,4-dioxo-5-iodopyrimidin-1-yl)-4α-hydroxy-5β-hydroxymethylcyclopentane-1,2-diol.14. The compound of claim 2 which is3β-(2,4-dioxo-5-iodopyrimidin-1-yl)-4β-hydroxy-5β-hydroxymethylcyclopentane-1,2-diol.15. The compound of claim 2 which is3β-(2,4-dioxo-5-iodopyrimidin-1-yl)-4α-fluoro-5β-hydroxymethylcyclopentane-1,2-diol.16. The compound of claim 2 which is3β-(2,4-dioxo-5-iodopyrimidin-1-yl)-4β-fluoro-5β-hydroxymethylcyclopentane-1,2-diol.17. The compound of claim 2 which is3β-(2,4-dioxo-5-iodopyrimidin-1-yl)-4α,4β-difluoro-5β-hydroxymethylcyclopentane-1,2-diol.18. The compound of claim 2 which is3β-(6-aminopurin-9-yl)-4α-hydroxy-5β-hydroxymethylcyclopentane-1,2-diol.19. The compound of claim 2 which is3β-(6-aminopurin-9-yl)-4β-hydroxy-5β-hydroxymethylcyclopentane-1,2-diol.20. The compound of claim 2 which is3β-(6-aminopurin-9-yl)-4α-fluoro-5β-hydroxymethylcyclopentane-1,2-diol.21. The compound of claim 2 which is3β-(6-aminopurin-9-yl)-4β-fluoro-5β-hydroxymethylcyclopentane-1,2-diol.22. The compound of claim 2 which is3β-(6-aminopurin-9-yl)-4α,4β-difluoro-5β-hydroxymethylcyclopentane-1,2-diol.23. The compound of claim 2 which is3β-(2-amino-6-oxopurin-9-yl)-4α-hydroxy-5β-hydroxymethylcyclopentane-1,2-diol.24. The compound of claim 2 which is3β-(2-amino-6-oxopurin-9-yl)-4β-hydroxy-5β-hydroxymethylcyclopentane-1,2-diol.25. The compound of claim 2 which is3β-(2-amino-6-oxopurin-9-yl)-4α-fluoro-5β-hydroxymethylcyclopentane-1,2-diol.26. The compound of claim 2 which is3β-(2-amino-6-oxopurin-9-yl)-4β-fluoro-5β-hydroxymethylcyclopentane-1,2-diol.27. The compound of claim 2 which is3β-(2-amino-6-oxopurin-9-yl)-4α,4β-difluoro-5β-hydroxymethylcyclopentane-1,2-diol.28. A compound of claim 1 wherein A is hydroxy and C is hydrogen. 29.The compound of claim 28 which is3β-[2,4-dioxo-5-(2-bromovinyl)pyrimidin-1-yl]-4α-hydroxy-5.beta.-hydroxymethylcyclopentan-1α-ol.30. The compound of claim 28 which is3β-[2,4-dioxo-5-(2-bromovinyl)pyrimidin-1-yl]-4β-hydroxy-5β-hydroxymethylcyclopentan-1α-ol.31. The compound of claim 28 which is3β-[2,4-dioxo-5-(2-bromovinyl)pyrimidin-1-yl]-4α-fluoro-5β-hydroxymethylcyclopentan-1α-ol.32. The compound of claim 28 which is3β-[2,4-dioxo-5-(2-bromovinyl)pyrimidin-1-yl]-4β-fluoro-5β-hydroxymethylcyclopentan-1α-ol.33. The compound of claim 28 which is3β-[2,4-dioxo-5-(2-bromovinyl)pyrimidin-1-yl]-4α,4β-difluoro-5β-hydroxymethylcyclopentan-1α-ol.34. The compound of claim 28 which is3β-(2,4-dioxo-5-trifluoropyrimidin-1-yl)-4α-hydroxy-5β-hydroxymethylcyclopentan-1α-ol.35. The compound of claim 28 which is3β-(2,4-dioxo-5-trifluoropyrimidin-1-yl)-4β-hydroxy-5β-hydroxymethylcyclopentan-1α-ol.36. The compound of claim 28 which is3β-(2,4-dioxo-5-trifluoropyrimidin-1-yl)-4α-fluoro-5β-hydroxymethylcyclopentan-1α-ol.37. The compound of claim 28 which is3β-(2,4-dioxo-5-trifluoropyrimidin-1-yl)-4β-fluoro-5β-hydroxymethylcyclopentan-1α-ol.38. The compound of claim 28 which is3β-(2,4-dioxo-5-trifluoropyrimidin-1-yl)-4α,4β-difluoro-5.beta.-hydroxymethylcyclopentan-1α-ol.39. The compound of claim 28 which is3β-(2,4-dioxo-5-iodopyrimidin-1-yl)-4α-hydroxy-5β-hydroxymethylcyclopentan-1α-ol.40. The compound of claim 28 which is3β-(2,4-dioxo-5-iodopyrimidin-1-yl)-4β-hydroxy-5β-hydroxymethylcyclopentan-1α-ol.41. The compound of claim 28 which is3β-(2,4-dioxo-5-iodopyrimidin-1-yl)-4α-fluoro-5β-hydroxymethylcyclopentan-1α-ol.42. The compound of claim 28 which is3β-(2,4-dioxo-5-iodopyrimidin-1-yl)-4β-fluoro-5β-hydroxymethylcyclopentan-1α-ol.43. The compound of claim 28 which is3β-(2,4-dioxo-5-iodopyrimidin-1-yl)-4α,4β-difluoro-5β-hydroxymethylcyclopentan-1α-ol.44. A pharmaceutical composition useful for treating viral infections inmammals which comprises an effective amount of at least one compound ofclaim 1 or a pharmaceutically acceptable acid addition salt thereof anda pharmaceutically acceptable excipient.
 45. A method for treatingmammals for viral infections which comprises administering an effectiveamount of a pharmaceutical composition of claim 44.